The invention relates to a novel process and novel intermediates for the synthesis of certain non-nucleoside reverse transcriptase inhibitors.
The disease known as acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV), particularly the strain known as HIV-1. In order for HIV to be replicated by a host cell, the information of the viral genome must be integrated into the host cell""s DNA. However, HIV is a retrovirus, meaning that its genetic information is in the form of RNA. The HIV replication cycle, therefore, requires a step of transcription of the viral genome (RNA) into DNA. The transcription of the viral RNA into DNA is accomplished by an enzyme that has been aptly dubbed reverse transcriptase (RT). The HIV virion includes a copy of RT along with the viral RNA.
Reverse transcriptase has three known enzymatic functions. It acts as an RNA-dependent DNA polymerase, as a ribonuclease, and as a DNA-dependent DNA polymerase. Acting as an RNA-dependent DNA polymerase, RT transcribes a single-stranded DNA copy of the viral RNA. Acting as a ribonuclease, RT destroys the original viral RNA, and frees the DNA just produced from the original RNA. Finally, acting as a DNA-dependent DNA polymerase, RT makes a second, complementary DNA strand, using the first DNA strand as a template. The two strands form double-stranded DNA, which is integrated into the host cell""s genome by another enzyme called integrase.
Compounds that inhibit the enzymatic functions of HIV-1 reverse transcriptase will inhibit replication of HIV-1 in infected cells. Such compounds are useful in the prevention or treatment of HIV-1 infection in human subjects, as demonstrated by known RT inhibitors such as 3xe2x80x2-aziod-3xe2x80x2-deoxythymidine (AZT), 2xe2x80x2,3xe2x80x2-dideoxyinosine (ddI), 2xe2x80x2,3xe2x80x2-dideoxycytidine (ddC), d4T, 3TC, nevirapine, delavirdine, efavirenz and abacavir, the RT inhibitors thus far approved as drugs for use in the treatment of HIV infection.
As with any antiviral therapy, use of RT inhibitors in the treatment of HIV infection eventually leads to a virus that is less sensitive to the given drug. Resistance (reduced sensitivity) to these drugs is the result of mutations that occur in the reverse transcriptase segment of the pol gene. Several mutant strains of HIV have been characterised, and resistance to known therapeutic agents is due to mutations in the RT gene. Some of the most commonly observed mutant clinically are: the Y181C mutant, in which a tyrosine Y, at codon 181, has been mutated to a cysteine C residue, and K103N where the lysine K at position 103 has been replaced by asparagine N. Other mutants which emerge with increasing frequency during treatment with known antivirals include the single mutants V106A, G190A, Y188C, and P236L: and the double mutants K103N/Y181C, K013N/P225H, K103N/V108I and K103N/L100I.
As therapy of HIV infection using antivirals continues, the emergence of new resistant strains is expected to increase. There is therefore an ongoing need for new inhibitors of RT, with different patterns of effectiveness against the various mutants.
Of particular relevance to the present invention are the HIV-RT inhibitors disclosed by U.S. Pat. No. 6,420,359. These compounds, which are all dipyrido[3,2-b:2xe2x80x2,3xe2x80x2-e] [1,4]diazepin-6-ones bearing a 2-(quinolinyl)oxyethyl or a 2-(1-oxido-quinolinyl)oxyethyl group in the 8-position, have enhanced activity against certain clinically significant mutant strains of HIV-1. It is the object of the present invention to provide an alternative method for making the compounds disclosed by U.S. Pat. No. 6,420,359.
The invention provides an improved process for making compounds of the general formula I: 
wherein:
R2 is selected from the group consisting of H, F, Cl, C1-4 alkyl, C3-4 cycloalkyl and CF3;
R4 is H or Me;
R5 is H, Me or Et, with the proviso that R4 and R5 are not both Me, and if R4 is Me then R5 cannot be Et;
R11 is Me, Et, cyclopropyl, propyl, isopropyl, or cyclobutyl; and
Q is selected from the group consisting of: 
as well as pharmaceutically acceptable salts thereof.
The synthetic method of the invention commences from a starting compound of the formula II 
wherein R2, R4, R5 and R11 are as defined above with respect to compounds of the formula I and wherein X is a chlorine, iodine, or bromine, or a fluorosulfonate moiety selected from the group consisting of xe2x80x94OSO2F and xe2x80x94OSO2(CF2)nCF3 wherein n is an integer between 0 and 10. Processes for making starting compounds of the formula II wherein X is bromine are described in U.S. Pat. No. 6,420,359. Compounds wherein X is other than bromine can be made by analogous methods which will be readily apparent to those of ordinary skill in the art.
It is preferred to use a compound of the formula II wherein X is bromine.
The starting compound of the formula II initially undergoes a palladium-catalyzed coupling reaction wherein it is caused to arylate a malonate or malonate surrogate of the formula III 
wherein,
R12 is a cyano group or a group of the formula xe2x80x94COOR14, wherein R14 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl, and
R13 is a cyano group, a group of the formula xe2x80x94COOR15 (wherein R15 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl), a group of the formula xe2x80x94SO2R16 (wherein R16 is a C-1-4-alkyl group, phenyl, furyl, pyridyl or benzyl), a group of the formula xe2x80x94P(O)(OR17)2 (wherein R17 is phenyl, furyl or pyridyl) or a group of the formula xe2x80x94SOR18 (wherein R18 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl).
It is preferred to employ a malonate surrogate of the formula III 
wherein,
R12 is a cyano group or a group of the formula xe2x80x94COOR14, wherein R14 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl; and
R13 is a cyano group, a group of the formula xe2x80x94SO2R16 (wherein R16 is a C-1-4-alkyl group, phenyl, furyl, pyridyl or benzyl), a group of the formula xe2x80x94P(O)(OR17)2 (wherein R17 is phenyl, furyl or pyridyl) or a group of the formula xe2x80x94SOR18 (wherein R18 is a C-1-4-alkyl group, a C-1-4-alkyloxy-C-1-4-alkyl group group phenyl, naphthyl, thiophenyl, furyl, pyridyl, imidazole or benzyl).
The reaction of the compounds of the formulas II and III takes place in an organic solvent, in the presence of a palladium catalyst, a suitable ligand and strong base. Suitable solvents are, by way of non-limiting example, toluene, ethylbenzene, xylene, DMF, DMA, NMP, dioxane and THF, with toluene being preferred. Virtually any palladium catalyst may be used, such as, for example, Pd(OAc)2, PdCl2, Pd2dba3 and Pd on carbon, with Pd(OAc)2 being preferred. Suitable bases are, for example, the metal hydrides such as, for example, NaH, the metal alkoxides such as, for example, t-BuOK, t-BuONa and Na-tert-amylate, the metal carbonates such as, for example, Na2CO3, K2CO3 and CS2CO3, with NaH being preferred, and the metal phosphates such as, for example, K3PO4. When the reactant of the formula III is a malonate (compounds wherein R12 and R13 are both carboxylic acid ester groups) then suitable ligands will be t-Bu3P, one of the ligands described and claimed in U.S. Pat. No. 6,307,087, or a ferrocenyl phosphine such as described in U.S. Pat. Nos. 6,057,456 and 6,072,073. When the reactant of the formula III is not a malonate, but rather a malonate surrogate (a compound wherein R12 and R13 are not both carboxylic acid ester groups) the above-mentioned ligands may be employed and, in addition, a triarylphosphine such as, by way of non-limiting example, PPh3, o-Tol3P, p-Tol3P and o-Fur3P may also be employed. In such case the preferred ligand is PPh3.
The reaction is preferably carried out at elevated temperature, more preferably in the range between about 50 and 150xc2x0 C.
The above described reaction, which couples the compounds of the formulas II and III, yields an intermediate of the formula IV 
wherein R2, R4, R5, R11, R12 and R13 are as defined above.
Isolation of the intermediate of the formula IV before going on to the next process step is optional. It has been found that a one pot synthesis wherein the intermediate IV is not isolated is quite convenient. If the intermediate IV is not isolated and the residual base is a metal hydride, such as NaH, then it is advisable to quench the base with an agent such as isopropyl alcohol before going on to the next step.
If the intermediate of the formula IV contains sulfur or phosphorus (because R13 in the reactant of the formula III was a group of the formula xe2x80x94SO2R15 or xe2x80x94P(O)(OR16)2) then the next process step is a reductive cleavage of the sulfur or phosphorus-containing group. Methods for performing such reductive cleavage will be well known to those of ordinary skill in the art. For example, this might be accomplished by the use of Raney nickel or a dissolving metal reaction.
Subsequent to the reductive cleavage or, if the intermediate of formula IV does not contain sulfur or phosphorus, the intermediate of the formula IV is next hydrolyzed to yield a further intermediate of the formula V 
wherein R2, R4, R5 and R11 are as defined above and R19 is xe2x80x94COOH or, if the reactant of formula III was a malonate and mild hydrolysis conditions are employed, R19 may additionally be a group of the formula xe2x80x94COOR14 wherein R14 is as described above. The hydrolysis may be performed in a manner that will be conventional and readily apparent to those of ordinary skill in the art. For example, it may be accomplished using an aqueous base, such as NaOH, preferably at ambient temperature or above.
The intermediates of the formulas IV and V are believed to be novel and constitute a part of the invention.
Isolation of the intermediate V before going on to the next step is preferred.
Next, the carboxylic acid or ester intermediate of the formula V is reduced to yield an alcohol of the formula VI 
wherein R2, R4, R5 and R11 are as defined above. Reduction is carried out in a conventional manner that will be readily apparent to those of ordinary skill in the art. Regardless of whether the intermediate of the formula V is an acid or an ester, reduction may be accomplished using boranes, borohydrides or other metal hydrides or dissolving metal reductants, with boranes being preferred for the acids and borohydrides being preferred for the esters. If a borane is to be employed it is preferred to make it in situ from a borohydride, such as sodium borohydride, and an electrophilic reagent such as, for example HCl.
Finally, the alcohol of formula VI is converted to the final product of the formula I by a condensation reaction with a reactant of the formula 
This condensation may be accomplished in the manner described in U.S. Pat. No. 6,420,359.
The nature and scope of the invention will be better appreciated from the following examples.